FIELD OF THE INVENTION
The present invention relates to an industrially advantageous process for preparing tetrahydrofuran antifungals, in particular, posaconazole of formula I.
(Formula Removed)
The present invention further relates to improved processes for preparing key intermediates useful in the preparation of posaconazole.
BACKGROUND OF THE INVENTION
Posaconazole of formula I, chemically known as (2R-cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-( 1,2,4-triazol-1 -ylmethyl)-tetrahydrofuran-3-ylmethoxy]-phenyl]piperazin-l-yl]phenyl]-2-[l(S)-ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H-1,2,4-triazol-3-one,
(Formula Removed)
is an antifungal agent which is used against a wide range of fungal pathogens, including both yeasts and molds.
U.S. Patent No. 5,661,151 (herein referred to as '151) discloses several substituted tetrahydrofuran antifungal compounds, including posaconazole. The patent discloses several processes for the preparation of posaconazole. According to one process, posaconazole is prepared by condensation of toluene-4-sulfonic acid (-)-(4R-cis)-5-(2,4-difluorophenyl)-5-[l,2,4]triazol-l-ylmethyl-tetrahydro-3-furanmethyl ester with N-protected triazolone derivative of following formula,
(Formula Removed)
wherein SEM is 2-(trimethyl)silylethoxymethyl group
in presence of a strong base in an aprotic solvent to give the compound of following formula
(Formula Removed)
which is then deprotected using hydrochloric acid in methanol followed by N-alkylation with brosylated (2S,3R) alcohol of formula,
(Formula Removed)
wherein R represents hydroxyl protecting group (R = SEM, benzyloxymethyl) in presence of strong base in an aprotic solvent to give hydroxy protected posaconazole which is then deprotected using hydrochloric acid in methanol to give posaconazole of formula I, which is purified by column chromatography. In an alternative process, '151 discloses the preparation of posaconazole by condensing (3R-cis)-N-4-[4-[4-[[5-(2,4-difluorophenyl)tetrahydro-5-(l H-1,2,4-triazol-l-yl)methyl)-furan-3-yl]methoxy]-phenyl]-l-piperazinyl]-phenyl]-carbamic acid phenyl ester of following formula,
(Formula Removed)
with hydrazine hydrate in dioxane followed by cyclization in the presence of formamidine acetate in dimethylformamide to give a cyclized intermediate of following formula,
(Formula Removed)
which is further N-alkylated with brosylated (2S,3R) alcohol of formula
(Formula Removed)
wherein R represents hydroxyl protecting group (R = SEM, benzyloxymethyl), in presence of cesium carbonate in an aprotic solvent to give hydroxy protected posaconazole, and is then converted to posaconazole.
The major drawback of the processes disclosed above is that N-alkylation is carried out on cyclized triazolone intermediate which requires a large excess of expensive alkylating agent, and results in a mixture of N-alkylated and O-alkylated posaconazole, necessitating laborious purification methods such as column chromatography which is a time-consuming and tedious process; especially for large samples hence it is not suitable for large scale production and further results in low yields of posaconazole.
In a still another methodology, '151 discloses a process for preparing posaconazole by reacting (3R-cis)-N-4-[4-[4-[[5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-yl)methyl)-furan-3-yl] methoxy]-phenyl] -1-piperazinyl]-phenyl]-carbamic acid phenyl ester with 2-[3-(2S,3S)-2-(benzyloxy)pentyl]formic acid hydrazide in the presence of 1-8-diaza bicyclo [5.4.0]undec-7-ene under heating to give benzyl ether of posaconazole of following formula,
(Formula Removed)
which on hydrogenolysis with palladium on carbon and formic acid in methanol
affords posaconazole which is further purified on preparative thin layer
chromatography.
US patent No. 5,403,937 discloses a process for the preparation of key
intermediate of posaconazole, specifically toluene-4-sulfonic acid 5-(2,4-difluoro-
phenyl)-5-[l,2,4]triazol-l-ylmethyl-tetrahydro-furan-3-ylmethyl ester as depicted
below.>
(Formula Removed)
The process disclosed in US patent 5,403,937 involves the use of n-butyl lithium during the preparation of oxazolidinone lithium salt, which is very expensive and extremely flammable. The process requires column chromatography purification at different stages to purify the intermediates which is tedious and lengthy process. The above drawbacks make the process unviable on commercial scale U.S. Patent No. 5,625,064 ('064) discloses a process for the preparation of posaconazole which involves the condensation of compound of formula II,
(Formula Removed)
with (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[(lH-l,2,4-triazol-l-yl)methyl]-
tetrahydro-3-furan methyl ester derivative of following formula
(Formula Removed)
wherein OB is a suitable leaving group selected from p-chlorobenzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride in the presence of base to give benzyl ether of posaconazole which is then deprotected either with palladium on carbon in the presence of formic acid or aqueous hydrobromic acid to form posaconazole.
The above process suffers from several drawbacks. In our hands we have found that the deprotection of benzyl ether of posaconazole in the presence of formic acid does not goes to completion or requires even more than 30-35 hours. This may lead to the degradation of the final product and may require tedious purification processes such as chromatographic purification or refluxing of the product with aqueous sodium hydroxide solution for another 24 hours as reported in the prior art. On the other hand, deprotection of benzyl ether of posaconazole with aqueous hydrobromic acid results in degradation of the compound of formula I necessitating laborious purification methods to purify posaconazole, hence resulting in loss of yield and purity.
In view of the above, there is thus an obvious need to find an efficient and industrially advantageous process for the synthesis of posaconazole which overcomes the problems associated with the prior art such as long reaction time, use of hazardous reagents and stringent reaction conditions and tedious purifications.
OBJECT OF THE INVENTION
One principle object of the invention is to provide a process for the preparation of highly pure posaconazole in high yield and reduced time cycle.
Another object of the present invention is to provide a cost effective, efficient, and industrially viable process for the preparation of posaconazole avoiding stringent reaction conditions.
Another object of the present invention to provide a process for the preparation of pure posaconazole wherein purification by column chromatography is avoided.
SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a process for the preparation of highly pure posaconazole of formula I
(Formula Removed)
which comprises:
a. debenzylating compound of formula II,
(Formula Removed)
using mineral acid, in the presence of noble metal catalyst, in an organic solvent, under hydrogen gas pressure to prepare compound of formula III,
(Formula Removed)
b. condensing the resulting compound of formula III with compound of formula
IV,
(Formula Removed)
wherein OB is a suitable leaving group selected from p-chlorobenzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride in the presence of suitable base in an organic solvent;
c. isolating posaconazole,
d. optionally purifying posaconazole.
Another aspect of the present invention provides a process for the preparation of posaconazole of formula I comprises:
a. reacting 4-(2,4-difluoro-phenyl)-4-oxo-butyric acid of formula V
(Formula Removed)
with methyltriphenylphosphonium bromide in the presence of sodium hexamethyldisilazane and a base to afford a compound of formula VI;
(Formula Removed)
b. purifying the compound of formula VI with C1-C7 hydrocarbon solvent;
c. reacting the compound of formula VI with chiral auxiliary in the presence of
an activating agent, tertiary amine base and 4-dimethylamino pyridine in an
inert solvent to afford a compound of formula VII,
(Formula Removed)
wherein Q* represents a chiral auxiliary
d. treating the compound of formula VII with 1,3,5-trioxane in the presence of
titanium tetrachloride, titanium isopropoxide and a tertiary amine base to
afford a compound of formula VIII,
(Formula Removed)
e. halocyclizing the compound of formula VIII in the presence of suitable
halogen, an amine base in an inert solvent to afford a compound of formula
IX,
(Formula Removed)
wherein X is selected from halogen such as iodo, chloro, bromo etc.
f. purifying the compound of formula IX with C1-C4 linear or branched alcoholic
solvents, C2-C8 linear or branched ethers and mixtures thereof,
g. reducing the compound of formula IX with a suitable reducing agent in an
organic solvent to afford compound of formula X
(Formula Removed)
wherein X is as defined above h. condensing the compound of formula X with alkali metal triazole in the presence of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone in polar aprotic solvent such as N,N-dimethylformamide and the like to afford a compound of formula XI
(Formula Removed)
i. reacting the compound of formula XI with a reagent having a suitable leaving group in the presence of a base in a suitable solvent to afford a compound of formula IV,
(Formula Removed)
wherein OB is a suitable leaving group selected from p-chlorobenzenesulfonyl
chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride
j. purifying the compound of formula IV by recrystallization from an organic
solvent selected from ethers, C1-C4 alcohols, C3-C7 linear, branched and cyclic
alkanes or mixtures thereof. k. converting the compound of formula IV to posaconazole. Yet another aspect of the present invention is to provide an improved process for the preparation of highly pure posaconazole of formula I which comprises: debenzylating the benzyl ether of posaconazole of formula XII,
(Formula Removed)
using a mineral acid in presence of a noble metal catalyst in an organic solvent, under hydrogen pressure, at a temperature of 20 °C to 80 °C; isolating posaconazole; optionally purifying posaconazole.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides processes for the preparation of posaconazole of formula I from a compound of formula II. In one embodiment the compound of formula II is debenzylated first and thereafter the resulting debenzylated compound of formula III is condensed with compound of formula IV. In one another embodiment the compound of formula II is condensed with compound of
formula IV first and thereafter the resulting compound is debenzylated to afford
posaconazole.
Typically, debenzylation of the compound of formula II is carried out using a
noble metal catalyst in the presence of mineral acid in an organic solvent
employing hydrogen gas pressure. Generally, hydrogen gas is applied at a
pressure of about 2 kg/cm2 to 8 kg/cm2. Preferably, the hydrogen pressure applied
is about 3 kg/cm2 to 6 kg/cm2.
Noble metal catalyst may be selected from Noble metal catalyst may be selected
from Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon,
rhodium-carbon, copper-chromium oxide, etc., and the like, most preferably
palladium on carbon is employed. Mineral acid can be selected from hydrochloric
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, more preferably
hydrochloric acid is. Organic solvent may be selected from alcoholic solvent such
as C1-C4 alcohols, dimethylformamide, dimethylsulfoxide, preferably methanol,
ethunol, propanol, n-butanol, isopropanol, dimethylsulfoxide and more preferably
methanol is employed.
The debenzylation reaction is usually conducted at a temperature of about 20 °C
to 80 °C. Preferably, the temperature is maintained during reaction is about 40 °C
to about 60 °C for a period of about 1 to 5 hours. The completion of reaction may
be monitored by TLC or HPLC. After completion of reaction, reaction mixture is
filtered to remove the catalyst. Solvent is distilled out and the resulting residue is
further dissolved in suitable aliphatic esters such as ethyl acetate and further
stirred for 1 to 2 hours at the reflux temperature of the solvent to afford
debenzylated compound of formula III.
Thereafter, the resulting debenzylated compound of formula III is condensed with
compound of formula IV in the presence of a base in an organic solvent, at
temperature of about 30 °C to the reflux temperature of the solvent to afford
posaconazole of formula I.
Base can be selected from an alkali or alkaline earth metal hydroxide, hydrides or
carbonates, for example, sodium hydroxide, potassium hydroxide, calcium
hydroxide, lithium hydroxide, sodium hydride, lithium hydride, potassium hydride
and the like, sodium carbonate, potassium carbonate, calcium carbonate, and the like. Organic solvent can be selected from polar aprotic or protic solvent preferably methanol, ethanol, isopropanol, dimethylformamide, dimethylsulfoxide, and the like or mixture thereof.
Preferably the condensation reaction is carried out in presence of sodium hydroxide in isopropyl alcohol or in dimethylsulfoxide at about 30 °C to about 80 °C. Normally, the condensation reaction is completed in about 3 to 15 hours. After completion of reaction, the reaction mass is cooled and diluted with water and stirred for sufficient time to precipitate posaconazole, which is then isolated by filtration.
Posaconazole so formed can further be purified by recrystallization using the solvent selected from C1-C4 linear or branched alcoholic solvents such as ethanol, methanol, n-propanol, isopropanol, tertiary butanol, acetonitrile, acetone, water and mixtures thereof, preferably methanol.
The key intermediate of formula IV may be procured from commercial source or prepared by the processes well known in art such as US patent No. 5,403,937 and Tetrahedron Letters, vol.37, No.32, pp 5657-5660 (1996) with modification which are reported herein for reference.
Typically, compound of formula IV can be prepared by initially reacting 4-(2,4-difluoro-phenyl)-4-oxo-butyric acid compound of formula V under wittig reaction conditions to give compound of formula VI.
Preferably a solution of methyltriphenylphosphonium bromide, sodium hexamethyldisilazane and base preferably alkali metal hydride in a suitable solvent selected from polar aprotic solvent is prepared at ambient temperature, followed by stirring the reaction mass at a temperature of about 40 °C to 55 °C. The reaction mass is then cooled to a temperature of below 0 °C and is added to the solution of compound of formula V in polar aprotic solvent at temperature about -75 °C to -80 °C. Alkali metal hydride base can be selected from sodium hydride, lithium hydride, potassium hydride and the like, most preferably sodium hydride Polar aprotic solvent can be selected from 1,4-dioxane, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethylsi lfoxide
and mixtures thereof, preferably polar aprotic solvent is tetrahydrofuran. The reaction mass is then heated to a temperature of 60-80 °C with stirring for 8-14 hours. Completion of reaction may be monitored by TLC or HPLC and after completion of the reaction, mixture is cooled to 10-20 °C and quenched with an alcoholic solvent preferably methanol. The resulting mixture is then treated with an aqueous solution of citric acid optionally with hydrochloric acid and extracted with aliphatic esters preferably with ethyl acetate to remove side products present as impurities. The crude product so formed is further purified by treatment with suitable aqueous base like potassium hydroxide, sodium hydroxide and the like to prepare base addition salt of compound of formula VI followed by neutralization of the salt with dilute mineral acid such as hydrochloric acid in the presence of C|-C7 hydrocarbon solvent to extract the product in organic layer to yield compound of formula VI in high yield and purity. C1-C7 hydrocarbon solvent is selected from n-pentane, n-hexane, n-heptane and the like, preferably n-hexane. It has been found that using alkali metal hydride base such as sodium hydride in combination with sodium hexamethyldisilazane facilitates easy isolation of the product from the reaction mass as compared to the prior art processes. The compound of formula VI is then treated with known activating agents such as oxalyl chloride, thionyl chloride, carbonylditriazole or oxalylditriazole, pivaloyl chloride etc., preferably pivaloyl chloride in the presence of tertiary amine base such as triethylamine in an inert solvent such as, dichloromethane, tetrahydrofuran and the like to afford activated intermediate. The activated intermediate is then treated insitu with a chiral auxiliary in the presence of base like 4-dimethyl amino pyridine in an inert solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or mixtures thereof at ambient temperature to afford a compound of formula VII.
Preferably the chiral auxiliary used is (R)-benzyl-2-oxazolidinone. The reaction mixture is heated to a temperature of about 35-55 °C, more preferably at about 45-50 °C and further stirred for a period of about 3-6 hours. Completion of the reaction may be monitored by TLC or HPLC. After completion of reaction, reaction mixture is cooled and quenched with a suitable quenching agent.
Suitable quenching agent may be selected from ammonium chloride, inorganic acids selected from sulfuric acid, hydrochloride acid, and the like or organic acid selected from acetic acid, formic acid, benzoic acid, and the like or any other reagent selected from ketones such as acetone, ethylmethyl ketone, methylisobutyl ketone.
The present invention is advantageous as it teaches the direct use of chiral auxiliary in presence of 4-dimethyl amino pyridine without converting it to its lithium salt using highly inflammable and expensive n-butyl lithium as disclosed in prior art.
Compound of formula VII is then converted to compound of formula VIII by treating the compound of formula VII with titanium tetrachloride and titanium isopropoxide in the presence of halogenated solvent selected from chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane and the like, preferably dichloromethane at a temperature of below 0 °C. To the resulting solution a tertiary amine base such as triethylamine, diisopropylethylamine, preferably triethyl amine is added at a temperature of about -5 to 0 °C to prepare metal enolates of compound of formula VII. Metal enolates of compound of formula VII is further treated insitu with a solution of 1,3,5-trioxane in halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane and the like, preferably dichloromethane at -5 to 0 °C. Preferably a solution of 1,3,5-trioxane in a halogenated solvent is added to the solution of metal enolate of compound of formula VII. It is advantageous to add another lot of titanium tetra chloride after the addition 1,3,5-trioxane solution.
Completion of the reaction may be monitored by TLC. After completion of reaction, reaction mixture is quenched with a suitable quenching agent like aqueous ammonium chloride to give compound of formula VIII. In the present invention, the compound of formula VIII is further halocyclized to give compound of formula IX. Preferably compound of formula VIII is dissolved in an inert solvent selected from polar aprotic solvent such as acetonitrile, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, ethyl acetate and mixtures thereof and treated with halogen such as iodine, chlorine, bromine and
the like, preferably with iodine in the presence of an amine base such as pyridine while maintaining the temperature at about -5 to 5°C. The temperature of reaction mass is maintained at ambient temperature for a time sufficient to form compound of formula IX. After completion of reaction, reaction mixture is quenched with a suitable quenching agent and further extracted with a non polar solvent such as an ethereal solvent preferably diisopropyl ether.
Compound of formula IX is then recrystallized using suitable solvent selected from ethereal solvents such as diisopropyl ether, t-butyl methyl ether, and the like; C1-C4 linear and branched alcoholic solvents such as ethanol, methanol, n-propanol, isopropanol, tertiary butanol and the like or mixtures thereof. Preferably diisopropyl ether, ethanol or a combination thereof is used.
Compound of formula IX is then reduced to compound of formula X using a hydride reducing agent in the presence of polar protic and aprotic solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, ethyl acetate and mixtures thereof, preferably ethanol, tetrahydrofuran and mixture thereof is employed. The reaction is preferably performed at a temperature of -5 to 0 °C. Completion of reaction may be monitored by TLC. Thereafter the reaction mixture is quenched with a suitable quenching agent and further extracted with a non polar solvent such as an ethereal solvent preferably diisopropyl ether to afford compound of formula X. Compound of formula X is further condensed with alkali metal triazole preferably 1,2,4-sodium triazole in presence of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone in polar aprotic solvent such as N,N-dimethylformamide at a temperature of 90-110°C for time sufficient to convert to compound of formula XI.
The hydroxyl group of compound of formula XI is further converted to a suitable leaving group to give compound of formula IV.
Preferably compound of formula XI is dissolved in an inert solvent followed by addition of an amine base such as 4-dimethyl amino pyridine, pyridine, triethylamine preferably 4-dimethyl amino pyridine at ambient temperature. Solvent can be selected from halogenated hydrocarbons such as carbon
tetrachloride, chloroform, tetrachloroethene, trichloroethene, dichloroethene, 1,1-dichloroethene, 1,3-dichloropropene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 3-chlorotoluene, dichloromethane; aliphatic esters such as ethyl acetate; tetrahydrofuran, toluene and mixtures thereof, preferably dichloromethane is used. The reaction mass is cooled to -5 to 10 °C preferably 0 to 5 °C and treated with a suitable leaving group such as p-chlorobenzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride and the like, preferably p-chlorobenzene sulfonyl chloride. The reaction mass is stirred for sufficient time preferably till reaction completion at ambient temperature. Compound of formula IV can further be crystallized using suitable solvent selected from ethers such as diisopropyl ether, t-butyl methyl ether, and the like; C1-C4 alcohols such as ethanol, methanol, n-propanol, isopropanol, tertiary butanol and the like; C3-C7 linear, branched and cyclic alkanes or mixtures thereof in high purity, without the need to use column chromatography as reported in prior art. Most preferably solvent of crystallization is ethanol. According to another embodiment, posaconazole of formula I is prepared by the condensation of compound of formula II with compound of formula IV to afford benzyl ether of posaconazole of formula XII, which is further debenzylated to afford posaconazole.
Particularly, the compound of formula II is condensed with the compound of formula IV in the presence of base in an organic solvent, at temperature of about 30 °C to the reflux temperature of organic solvent to afford compound of formula XII, which is then debenzylated to posaconazole.
Base can be selected from an alkali or alkaline earth metal hydroxide, hydrides or
carbonates, for example, sodium hydroxide, potassium hydroxide, calcium
hydroxide, lithium hydroxide, sodium hydride, lithium hydride, potassium hydride
and the like, sodium carbonate, potassium carbonate, calcium carbonate, and the
like. Organic solvent can be selected from polar aprotic or protic solvent
preferably methanol, ethanol, isopropanol, dimethylformamide,
dimethylsulfoxide, and the like or mixture thereof.
One another embodiment of the present invention relates to an improved process for the preparation of posaconazole of formula I, by debenzylating benzyl ether of posaconazole of formula XII using a noble metal catalyst in the presence of mineral acid in an organic solvent, under hydrogen pressure, at a temperature of 20-80 °C.
Noble metal catalyst may be selected from Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., and the like, preferably the noble metal catalyst is palladium on carbon. Mineral acid can be selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, more preferably hydrochloric acid, hydrobromic acid and most preferably hydrochloric acid. Organic solvent may be selected from alcoholic solvent such as C1-C4 branched or linear aliphatic alcohols, dimethylforrnamide, dimethylsulfoxide, more preferably organic solvent is methanol, ethanol, propanol, n-butanol, isopropanol, dimethylsulfoxide and most preferably the organic solvent is methanol.
Preferably the reaction is performed at a hydrogen gas pressure of about 2 kg/cm to 8 kg/cm", preferably the hydrogen gas pressure is about 3 kg/cm to 6 kg/cm . The reaction is conducted at a temperature of about 20 °C to 80 °C, preferably at a temperature of about 40 °C to 60 °C for a period of 3 to 7 hours. The completion of reaction may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC). After completion of reaction, reaction mixture is filtered to remove the catalyst. The solvent is distilled out and the resulting residue is further dissolved in a suitable alcoholic solvent. The suitable alcoholic solvent may be selected from C1-C4 branched or linear aliphatic alcohols, more preferably methanol, ethanol, propanol, n-butanol, isopropanol, tertiary butanol and the like and most preferably tertiary butanol. Thereafter, the reaction mass is treated with a base preferably sodium hydroxide in an amount sufficient to adjust the pH of the reaction mixture, preferably, to about 6 to about 7 to isolate the posaconazole of formula I in high yield and purity.
The compound of formula I may be purified by recrystallization using suitable
solvent selected from C1-C4 alcohol such as ethanol, methanol, n-propanol,
isopropanol, tert. butanol, acetonitrile, acetone, water and mixtures thereof,
preferably methanol.
Use of mineral acid during hydrogenation reaction is advantageous because
reaction is completed in lesser time as compared to the prior art processes and
hence degradation of product and impurity formation is reduced.
The starting compound that is benzyl ether of posaconazole of compound of
formula XII may be prepared by the process reported in the prior art such as U.S.
Patent No. 5,625,064 etc or by the processes of the present invention.
Wherever required the intermediates and final compound posaconazole can be
treated with activated charcoal or silica gel to improve the color and quality of the
material. Isolation and purification of the compounds and intermediates described
can be effected, if desired, by any suitable separation or purification procedure
such as, for example, filtration, extraction, crystallization, or a combination of
these procedures. Specific illustrations of suitable separation and isolation
procedures can be had by reference to the examples herein below. However, other
equivalent separation or isolation procedures could, of course, also be used.
The following examples exemplify various aspects of the invention.
EXAMPLES
Example 1: Preparation of posaconazole
Step a) Preparation of (1S)-(2S)-2-(l-ethyl-2-hydroxy-propvn-4-{4-|4-(4-
hvdroxy-phenyl)-piperazin-l-vl|-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one
2-(2(S)-Benzyloxy-1 -ethyl-propyl)-4- {4-[4-(4-hydroxy-phenyl)-piperazin-1 -yl]-
phenyl}-2,4-dihydro-[l,2,4]triazol-3-one (30g) was taken in 5N hydrochloric acid
(60 ml) in methanol (300ml), and was hydrogenated for 2-3 hours under a
hydrogen pressure of 4 kg/cm2 at 50 °C in the presence of palladium on carbon
(10%, 3g). After completion of reaction (monitored by TLC), the catalyst was
filtered off and catalyst was washed with methanol (60 ml). The combined filtrate
was concentrated and the resulting mass was dissolved in ethyl acetate (600ml)
and refluxed for 1 hour. The resulting mixture was cooled, filtered to obtain 26g of the title compound having purity of 98.0% by HPLC. b) Preparation of posaconazole
To a stirred solution of (lS)-(2S)-2-(l-ethyl-2-hydroxy-propyl)-4-{4-[4-(4-hydroxy-phenyl)-piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one obtained above in dimethyl sulfoxide (140ml), a solution of sodium hydroxide (5.15g) in water was added at ambient temperature and stirred for 15 minutes. The reaction mixture was cooled to 10 °C and (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[(1H-1,2,4-triazole-1 -yl)methyl]-tetrahyro-3-furanmethanol-4-chlorobenzenesulphonate (30.0 g) was added. The temperature of the reaction mass was raised to 35-40 °C with stirring for 10-12 hours. To the resulting solution, water was added dropwise and further stirred for 60 minutes. The resulting mixture was filtered to obtain 36.4 g of the crude title compound as a white solid having purity of 97.0% by HPLC. The crude posaconazole was taken in methanol (360ml) and was stirred at reflux temperature for 30 minutes followed by cooling at ambient temperature. The precipitated product was filtered and washed with chilled methanol (50ml) and dried to obtain 32g of the title compound having purity of 99.5% by HPLC. Example 2: Preparation of posaconazole
a) Preparation of (lS)-(2S)-2-(l-ethyl-2-hydroxy-propyl)-4-{4-[4-(4-hydroxy-phenyl)-piperazin-1 -yl] -phenyl}-2,4-dihydro-[1,2,41 triazol-3-one (lS)-(2S)-2-(2-benzyloxy-l-ethyl-propyl)-4-{4-[4-(4-hydroxy-phenyl)-piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazole-3-one (6.5g) was taken in 5N hydrochloric acid (13ml) in methanol (65ml) and was hydrogenated for 2-3 hours under a hydrogen gas pressure of 4 kg/cm2 at 50 °C in the presence of palladium on carbon (10%, 0.65g). After completion of reaction (monitored by TLC), the catalyst was filtered off and washed with methanol (15ml). The combined filtrate was concentrated to obtain a residue. Residue was dissolved in ethyl acetate (65ml) and refluxed for 1 hour. The resulting mixture was cooled, filtered to obtain 5.3g of the title compound as a white solid having purity of 98.0% by HPLC.
b) Preparation of posaconazole
To a stirred solution of (lS)-(2S)-2-(l-ethyl-2-hydroxy-propyl)-4-{4-[4-(4-hydroxy-phenyl)-piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazol-3-one (5g) in isopropyl alcohol (50ml), a solution of sodium hydroxide (1.44g) in water was added at ambient temperature and stirred for 15 minutes. To the resulting mixture (-)-(5R-cis)-5-(2,4-difluoro-phenyl)-5-[(l H-1,2,4-triazole-1 -yl)methyl]-tetrahyro-3-furanmethanol-4-chloro- benzene sulphonate (6.5g) was added, raising the temperature to 70-80 °C and stirred at the same temperature for 6-7 hours. The resulting mixture was cooled, filtered to obtain 7.5g of the title compound as a white solid having purity of 97.0% by HPLC. Purification
The crude posaconazole (7.5g) was taken in methanol (75ml) and was stirred at reflux temperature for 30 minutes followed by cooling at ambient temperature. The precipitated product was filtered and washed with chilled methanol (15ml) and dried to obtain 6g of posaconazole having purity of 99.5% by HPLC. Example 3: Preparation of benzyl ether of posaconazole. To a stirred solution of (lS)-(2S)-2-(2-benzyloxy-l-ethyl-propyl)-4-{4-[4-(4-hydroxy-phenyl)-piperazin-l-yl]-phenyl}-2,4-dihydro-[l,2,4]triazole-3-one (1 Og) in dimethyl sulfoxide (100ml), a solution of sodium hydroxide (1.3g) in water (5ml) was added at ambient temperature and stirred for 15 minutes. To the resulting mixture (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[( 1H-1,2,4-triazole-1 -yl) methyl]-tetrahyro-3-furanmethanol-4-chlorobenzene sulphonate (10.0 g) was added, raising the temperature to 35-45° C and stirred at the same temperature for 10-12 hours. To the resulting solution water was added and stirred for 60 minutes. The resulting mixture was filtered to obtain 12.5g of the title compound having purity of 97.0% by HPLC. Example 4: Preparation of posaconazole
Benzyl ether of posaconazole (12.5g) was taken in 5N hydrochloric acid (25ml) in methanol (125ml), and was hydrogenated for 4-5 hours under a hydrogen gas pressure of 4 kg/cm2 at 50 °C in the presence of palladium on carbon (10%, 1.2g). After completion of hydrogenation (monitored by TLC), the catalyst was filtered
off and washed with methanol (25ml). The combined filtrate was concentrated to obtain a residue. Residue was dissolved in tert. butanol (250ml) and pH of the reaction mixture was adjusted to 6-7 with 47V sodium hydroxide solution to give l0g of crude title compound having purity of 93.5% by HPLC. Purification
Crude posaconazole obtained above was taken in methanol (100ml) and was stirred at reflux temperature for 30 minutes followed by cooling at ambient temperature. The precipitated product was filtered and washed with chilled methanol (20ml) and dried at 50 °C to obtain 7g of the title compound having purity of 99.5% by HPLC.
Example 5: Preparation of (-)-(5R-cis)-5-(2,,4-difluoro-phenyl)-5-[(1H-l,2,4-triazole-l-yl)methyl]-tetrahyro-3-furanmethanol-4-ehlorobenzene sulphonate Step a) Preparation of 4-(2,4-difluoro-phenyl)-pent-4-enoic acid To a stirred suspension of methyltriphenylphosphonium bromide (668g) in tetrahydrofuran (1400ml), solution of sodium hexamethyldisilazane (35%, 850ml) in tetrahydrofuran was added at 20-30 °C under nitrogen atmosphere. To the resulting suspension sodium hydride (35g) was added at 20-30 °C. The resulting mixture was further stirred for 90 minutes at 45-50 °C. The solution was cooled to -78 °C and a solution of 4-(2,4-difluoro-phenyl)-4-oxo-butyric acid (200 g) in tetrahydrofuran (600 ml) was added and stirring was continued for 1 -2 hours at 0 °C. The reaction mixture was slowly heated to 65-75 °C and further stirred for 10-12 hours at the same temperature. After completion of reaction (monitored by TLC), the reaction was cooled to 10-20 °C and quenched with methanol. The resulting mixture is diluted with an aqueous solution of citric acid and further stirred for 30 to 60 minutes. The so-formed mixture was extracted with ethyl acetate (1500ml). The organic layer was separated and distilled off to obtain an oily mass which was treated with aqueous potassium hydroxide (16% w/w) to adjust pH of reaction mass to 10-11. The aqueous layer was washed with dichloromethane (2x 1000ml) and ethyl acetate (1000ml) and thereafter treated with 5N hydrochloric acid to adjust pH of reaction mixture to 2-3. The resulting product was extracted with hexane (2x1500ml) and the combined organic layer
was washed with brine. The solvent was removed to provide 160g of the title
compound as a white solid having purity of 99.0% by HPLC.
Step b) Preparation of (4R)-4-benzyl-3-[4-(2.4-difluorophenyl)-pent-4-enoyl]-
oxazolidin-2-one
To a stirred solution 4-(2,4-difluorophenyl)-pent-4-enoic acid (150g) in dichloromethane (1500ml), triethylamine (146.6 g) was added at ambient temperature. The reaction mixture was cooled to 10 °C and pivaloyl chloride (85 ml) was added dropwise raising the temperature to 20-25 °C and stirred at the same temperature for 90 minutes. To the resulting solution (R)-benzyl-2-oxazolidinone (110.4g) and a mixture of 4-dimethyl amino pyridine (35.lg) in A^A'-dimethylformamide (56.1ml) was added at ambient temperature. The resulting mixture was warmed to 45-50 °C and stirred for 4-5 hours at the same temperature. After completion of reaction (monitored by TLC), reaction mass was cooled and quenched with sulfuric acid (2%, 500 ml). The organic layer was separated and subsequently washed with hydrochloric acid (IN, 500 ml) and sodium hydroxide (2 N, 500 ml). The organic layer was separated and distilled off to obtain a residue which was further treated with a mixture of activated carbon, silica gel in diisopropyl ether, stirred for 30 minutes and filtered. The solvent was removed to obtain 210g of the title compound having purity of 98.0% by HPLC. Step c) Preparation of (-)(2R)-(4R)-4-benzyl-3-[4-(2,4-difluorophenyl)-2-hydroxymethyl-pent-4-enoyl]-oxazolidin-2-one
To a stirred solution of (4R)-4-benzyl-3-[4-(2,4-difluorophenyl)-pent-4-enoyl]-oxazolidin-2-one (210g) in dichloromethane (1730 ml), titanium tetrachloride (108 ml) followed by titanium isopropoxide (159 ml) was added drop wise at -5 to 0 °C. To the resulting solution triethylamine (114g) was added slowly in 60 minutes while maintaining the temperature at 0 °C, the mixture was heated at 14-15 °C and further stirred for 60 minutes. The reaction mixture was cooled to 0 °C and a solution of 1,3,5-trioxane (103 g) in dichloromethane (250ml) was added at same temperature. To the resulting mixture titanium tetrachloride (171ml) was added while maintaining the temperature below -10 °C and further stirred to obtain a clear solution. After completion of reaction (monitored by TLC), reaction
mass was quenched with aqueous ammonium chloride solution. The organic layer was separated and washed with saturated ammonium chloride solution then treated with activated carbon and silica gel. The organic layer was filtered and solvent was removed to obtain 24 lg of the title compound.
Step d) Preparation of (-)(5R-cis)-(4R)-4-benzyl-3-[5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-furan-3-carbonyl]-oxazolidin-2-one To a stirred solution of (-)(2R)-(4R)-4-benzyl-3-[4-(2,4-difluorophenyl)-2-hydroxymethyl-pent-4-enoyl]-oxazolidin-2-one (24lg) in acetonitrile (2410 ml), iodine pellets (346 g) were added at ambient temperature. To the resulting mixture pyridine (108 ml) was added dropwise in 60 minutes while maintaining the temperature at 0 °C, the reaction mixture was heated to ambient temperature and stirred for 5 hours. After completion of reaction (monitored by TLC), reaction mass was cooled and quenched with of sodium thiosulfate (35%w/v, 2000 ml). The product was extracted with diisopropyl ether (1800ml) and subsequently washed with demineralized water (1000ml) and hydrochloric acid (IN, 1000 ml). The organic layer was separated and dried over sodium sulfate. The solvent was evaporated to obtain a solid residue. The solid residue was dissolved in ethanol (720ml) and stirred for 5 hours. The resulting mixture was cooled, filtered and washed the compound with ethanol to obtain 1 OOg of the title compound as a white solid having purity of 99.0% by HPLC.
Step e) Preparation of (-)(5R-cis)-5-(2,4-difluorophenyl)-5-
(iodomethyl)tetrahydro-3-furanmethanol
To a stirred solution of (-)(5R-cis)-(4R)-4-benzyl-3-[5-(2,4-difluorophenyl)-5-
(iodomethyl)tetrahydro-furan-3-carbonyl]-oxazolidin-2-one (100g)in
tetrahydrofuran (700 ml) and ethanol (300ml), lithium borohydride (458 ml) was added dropwise for a period of one hour at -5 to 0 °C. The resulting slurry was stirred for 2-3 hours at the same temperature. After completion of reaction (monitored by TLC), reaction mass was cooled and quenched with saturated ammonium chloride solution. The product was extracted with diisopropyl ether (2x500ml) and subsequently washed with demineralized water (500ml) and brine. The organic layer was separated and solvent was evaporated to provide a solid
having purity of 99.90% by HPLC.
residue. The solid residue was dissolved in diisopropyl ether (550ml) and stirred for 1 hour at 0 °C and thereafter filtered. The solvent was evaporated to obtain 70g of the title compound as a white solid having purity of 97.0% by HPLC. Step f) Preparation of (-)-(5R-cis)-5-(2,4-difluoro-phenyl)-5-[1H-l,2,4-triazole-1-yl) methyll-tetrahyro-3-furanmethanol
To a solution of (-)(5R-cis)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanmethanol (70g) in Af,iV-dimethylformamide (700 ml), 1,2,4-sodium triazole (90g) and l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (17.7 ml) were added at ambient temperature. The resulting mixture was heated to 100 °C and stirred for 24 hours. After completion of reaction (monitored by TLC),the reaction mass was cooled and quenched with demineralized water. The product was extracted with dichloromethane (2x500ml). The organic layer was treated with 6N hydrochloric acid (400 ml). The layers were separated and pH of the aqueous layer is adjusted to 8-9 with aqueous sodium hydroxide (50% w/v). The product from aqueous layer was extracted with ethyl acetate (2x500ml) and subsequently organic layer was washed with brine and dried over sodium sulfate. The solvent was removed to obtain 42g of the title compound. Step g) Preparation of (-)-(5R-cis)-5-(2,4-difluorophenyl)-5[1H-1,2,4-triazole-l-yl)methyl]-tetrahyro-3-furanmethanol-4-chlorobenzene sulphonate To a solution of (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-[(lH-l,2,4-triazole-l-yl) methyl]-tetrahyro-3-furanmethanol (42g) in dichloromethane (420ml), 4-dimethylamino pyridine (30g) was added. The reaction mixture was cooled to 0 °C and 4-chlorobenzenesulfonylchloride (44.77g) was added while maintaining the temperature at 0-5 °C. The resulting mixture was stirred for 3 hours at ambient temperature. After completion of reaction (monitored by TLC), reaction mass was washed with (2x300ml) of 5N solution of hydrochloric acid and saturated solution of sodium bicarbonate (300ml). The organic layer was separated and dried over sodium sulfate. The solvent was evaporated and the residue was dissolved in ethanol (300ml) and stirred for 4 hours. The resulting mixture was cooled, filtered and washed with ethanol to obtain 33.6g of the title compound as a white solid having purity of 99.90% by HPLC.

WE CLAIM
1. A process for the preparation of highly pure posaconazole of formula I
(Formula Removed)
which comprises:
a. debenzylating compound of formula II,
(Formula Removed)
using mineral acid in an organic solvent in the presence of noble metal catalyst under hydrogen gas pressure to prepare compound of formula III,
(Formula Removed)
b. condensing the compound of formula III with compound of formula IV,
(Formula Removed)
wherein OB is a suitable leaving group selected from p-chlorobenzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride in the presence of suitable base and organic solvent;
c. isolating posaconazole,
d. optionally purifying posaconazole.
2. The process according to claim 1, wherein in step a) the mineral acid is
selected from hydrochloric acid, hydrobromic acid, hydroiodic acid and
sulfuric acid and noble metal catalyst is selected from platinum oxide,
palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide and the like.
3. The process according to claim 1, wherein in steps a) and b), the organic solvent is selected from C1-C4 branched or linear aliphatic alcohols, dimethylformamide, dimethylsulfoxide or a mixture thereof.
4. The process according to claim 1, wherein in step b), the base is selected from alkali or alkaline earth metal hydroxides, hydrides or carbonates like sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, calcium carbonate.
5. A process for the preparation of posaconazole of formula I which comprises: debenzylating the benzyl ether of posaconazole of formula XII,
(Formula Removed)
using mineral acid in an organic solvent in the presence of a noble metal
catalyst under hydrogen gas pressure to prepare posaconazole;
optionally purifying posaconazole by recrystallization using suitable solvent
selected from C1-C4 alcohol such as ethanol, methanol, n-propanol,
isopropanol, tertiary butanol, acetonitrile, acetone, water and mixtures thereof;
and
isolating highly pure posaconazole therefrom.
6. The process according to claim 5, the mineral acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid; noble metal catalyst is Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., and the like; and organic solvent is selected from C1-C4 branched or linear aliphatic alcohols, dimethylformamide, dimethylsulfoxide or a mixture thereof.
7. A process for the preparation of posaconazole of formula I which comprises: a. reacting 4-(2,4-difluoro-phenyl)-4-oxo-butyric acid of formula V
(Formula Removed)
with methyltriphenylphosphonium bromide in the presence of sodium hexamethyldisilazane and a base to afford a compound of formula VI,
(Formula Removed)
b. purifying the compound of formula VI with C 1 -C7 hydrocarbon solvent,
c. reacting the compound of formula VI with chiral auxiliary in the presence
of an activating agent, tertiary amine base and 4-dimethylamino pyridine
in an inert solvent to afford a compound of formula VII,
(Formula Removed)
wherein Q* represents a chiral auxiliary
d. treating the compound of formula VII with 1,3,5-trioxane in the presence
of titanium tetrachloride, titanium isopropoxide and a tertiary amine base
to afford a compound of formula VIII,
(Formula Removed)
wherein Q* is as defined above
e. halocyclizing the compound of formula VIII in the presence of suitable
halogen, an amine base in an inert solvent to afford a compound of
formula IX,
(Formula Removed)
wherein Q* is as defined above and X is selected from halogen such as iodo, chloro, bromo etc.

f. purifying the compound of formula IX with C1-C4 linear or branched
alcoholic solvents, C2-C8 linear or branched ethers and mixtures thereof,
g. reducing the compound of formula IX with suitable reducing agent in an
organic solvent to afford compound of formula X,
(Formula Removed)
wherein X is as defined above h. condensing the compound of formula X with alkali metal triazole in the presence of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone in polar aprotic solvent such as N,N-dimethylformamide and the like to afford a compound of formula XI,
(Formula Removed)
i. reacting the compound of formula XI with a reagent having a suitable leaving group in a suitable solvent in presence of a base to afford a compound of formula IV,
(Formula Removed)
j. purifying the compound of formula IV by recrystallization from solvent selected from ethers, C1-C4 alcohols, C3-C7 linear, branched and cyclic alkanes or mixtures thereof and
k. converting the compound of formula IV to posaconazole.
8. The process according to claim 7, wherein in step e), inert solvent is selected from acetonitrile, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, ethyl acetate and mixtures thereof.
9. The process according to claim 7, wherein in step g), solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, ethyl acetate and mixtures thereof.
10. The process according to claim 7, wherein in step i), solvent is selected from halogenated hydrocarbons, aliphatic esters; tetrahydrofuran, toluene and mixtures thereof; reagent is selected from p-chlorobenzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride and the like and base is selected from 4-dimethyl amino pyridine, pyridine or triethylamine.